Indian Journal of Pharmacology 2002; 34: 390-396 EDUCATIONAL FORUM

K.K. SHARMA et al.

SOME NEW CONCEPTS IN ANTIBACTERIAL DRUG THERAPY

K.K. SHARMA, H. SANGRAULA, P.K. MEDIRATTA*

Department of Pharmacology, B.P. Koirala Institute of Health Sciences, Dharan, Nepal.

*Department of Pharmacology, University College of Medical Sciences & G.T.B. Hospital, Delhi 110 095

Manuscript Received: 3.12.2001 Revised: 5.9.2002 Accepted: 14.9.2002

ABSTRACT The goal of antibacterial therapy is to eradicate tissues of infecting organisms. However, achievement
of desired outcome will depend on a number of drug-, pathogen- and patient-related factors. Neither
microbiological pharmacodynamic activity (as measured by minimum inhibitory concentration [MIC]
or minimum bactericidal concentration [MBC] in vitro conditions) nor pharmacokinetic data of drug in
the host alone can adequately describe the complex interaction between the antibacterial agent, the
invading bacteria and the host, culminating in successful bacterial elimination. Accumulating
contemporary data especially in the last one-and-half decades from in vitro studies, animal models of
infection and clinical trials have shown that bacterial killing may be described as a function of either
drug concentration (concentration-dependent killing; CDK) or time of exposure (time-dependent
killing; TDK). Since the duration of exposure is a function of drug disposition in the host and is
measured by pharmacokinetic parameters of serum drug concentration (Cmax), simple correlations
can be made to optimize antibacterial chemotherapy. These evidence-based correlations have shown
that Cmax and area under the curve (AUC) when integrated with an antibacterial pharmacodynamic
parameter of MIC or MBC, the ensuing kineto-dynamic hybrid parameters, like Cmax/MIC or AUC/MIC
ratios and the time during which the antibacterial concentration remains above the MIC or MBC (t >
MIC or MBC) become important determinants of deciding the dose regimens of an antibacterial agent
which shows CDK (e.g. aminoglycosides; fluoroquinolones; metronidazole) or TDK (β-lactam; macrolide;
oxazolidinone antibiotics) properties, respectively. The present communication describes how the
new concepts of CDK and TDK kinetics when considered and applied along with the property of post-
antibiotic effect (PAE), displayed by certain antibiotics can make the antibacterial therapy cost-
effective, safe and efficient. PAE not only can mediate an enhanced antibacterial efficacy but also
prevent emergence of bacterial resistance.

KEY WORDS Antimicrobial therapy concentration-dependent effect microbial resistance post-antibiotic effect
time-dependent effect

Introduction
Making antibacterial drug therapy effective, safe and
affordable has been the focus of interest during re-
cent years. Antibacterial therapy, since its dawn in
1940s, is changing constantly and in the last fifteen
years has undergone a tremendous change due to
evolvement of new concepts in the pharmacokinetics
of antibacterial agents and their pharmacodynamics
in microbes1. Previously antibacterial agents were
selected on the basis of their high degree of in vitro
activity but currently antibiotic (the term 'antibiotic'
has been used interchangeably with the terms 'anti-
microbial' and 'antibacterial') use is based on its ef-
fectiveness and cost in a given situation2. The impor-
tant new concepts, which determine antibiotic use,
revolve around the word "effectiveness". In the past,
three basic principles, which were taken into consid-
eration to define the effectiveness of an antibiotic
were: (a) its bacteriostatic or bactericidal activity, (b)
its spectrum of antibacterial activity, and (c) its phar-
macokinetic characteristics. However, in present day
and age a clinician should also appreciate the differ-
ence between "concentration-dependent killing (CDK)
dynamics" versus "time-dependent killing (TDK) dy-
namics" of an antibiotic alongwith post-antibiotic ef-
fect (PAE), if any. These new concepts have impor-

Correspondence: K.K. Sharma

e-mail: drkksharma2000@yahoo.com

tant ramifications on how to dose an antibacterial agent
to make it efficient, safe and free from the develop-
ment of bacterial resistance. Single dose
aminoglycoside therapy and constant-infusion beta-
lactam therapy are examples of applying these phar-
macokinetic and pharmacodynamic principles to the
clinical situation. Besides these, new understandings
also guide the switch in therapy from intravenous to
oral route. Conversion from intravenous (parenteral)
to oral route therapy based on these pharmacokinetic
principles is socio-economically effective and is well
accepted by patients. The present review describes
evolution of new concepts of CDK, TDK and PAE dy-
namics of antibacterial agents and would consider how
application of these parameters make an antibiotic
effective and safe.
Antibacterial action
Generally if an antibacterial agent has to display ac-
tivity against a specific organism, it must first reach
the site of infection, it then needs to penetrate the
target site in the bacteria, attach itself to the site in
an adequate concentration, and remain there for a suf-
ficiently long period of time such that the organism is
inhibited from carrying out its normal life functions3.
The pharmacodynamic properties or the correlation
of drug concentrations and the clinical effect, i.e. bac-
terial killing of a specific antibiotic class are thus an
integration of two related areas, pharmacokinetics and
its microbiological activity. As drug concentrations can-
not be measured at the biophase, i.e. the site of ac-
tion, in vitro microbiological surrogate markers, such
as the minimum inhibitory concentration (MIC) or mini-
mum bactericidal concentration (MBC) are typically
used as means of assessing these pharmacodynamic
relationships. In vitro continuous exposure of a rela-
tively small number of bacteria to constant levels of a
drug, however, can differ considerably from in vivo
conditions where large numbers of bacteria are usu-
ally exposed to fluctuating levels of an antibiotic. Pa-
rameters that more accurately describe the time course
of antibacterial activity in such a situation, as recent
studies have shown, include rate of bacterial killing at
different concentrations4,5 and the presence or absence
of persistent suppression of bacterial growth follow-
ing antibiotic exposure after the agent has been to-
tally washed out from bacterial environment4-6. The
latter phenomenon is also referred to as the PAE7. It
is, therefore inappropriate to choose an antibiotic or
NEW CONCEPTS IN ANTIBACTERIAL THERAPY 391
antibiotic regimen based solely on the microbiologi-
cal activity or pharmacokinetics. Instead these agents
should be selected based on their individual
pharmacodynamic properties which should be corre-
lated with their pharmacokinetic profile.
Post-antibiotic effect (PAE)
PAE is defined as persistent suppression of bacte-
rial growth after a brief exposure (1 or 2 h) of bacteria
to an antibacterial agent even in the absence of host
defence mechanisms7-9. In PAE, inhibition of bacte-
rial growth is seen when either the antibacterial agent
is no longer present in bacterial medium or if present,
its concentration is well below the MIC. Variables that
affect PAE include the antibiotic type (vide infra), con-
centration and duration of antibiotic exposure, bac-
terial species and strain under investigation and cul-
ture media used10. This phenomenon was for the first
time described for quinolones and aminoglycosides8,9.
Ciprofloxacin, ofloxacin and lomefloxacin were found
to be similar in producing PAE of about 2 h in Gram-
negative and Gram-positive bacteria when exposed
for 1 h to antibiotic concentrations 4-fold greater than
MIC11. The duration of PAE was further increased
when the time of fluoroquinolones exposure was in-
creased to 2 h. The PAE for fluoroquinolones ap-
pears to be a concentration-dependent parameter9,12.
The newer fluoroquinolone compounds have been re-
ported to have PAEs of 1 to 6 h depending on the
pathogen and drug studied13,14. For aminoglycosides,
it was similarly noted that an initial high antibiotic
concentration and increased time of exposure pro-
longs the PAE; therefore with a high, single, daily
gentamicin dose, the PAE can be as long as
5-10 h 8,15. The measured duration of PAE was found
to be longer in vivo than in vitro and was also seen in
neutropenic animals15. The PAE was further extended
by higher doses of aminoglycosides and concurrent
administration of cell wall active antibiotics15,16. Later
studies revealed PAE activity in chemotherapeutic
agents, such as metronidazole and rifampicin16. Out
of all these drugs which showed PAE phenomenon,
rifampicin was demonstrated to have two important
features: (1) Unlike ciprofloxacin which did not show
synergistic prolongation of PAE of other drugs,
rifampicin was observed to prolong PAE in a
synergistic fashion when combined with other PAE -
producing agents; and (2) it had a prolonged and per-
sistent PAE activity17. It is because of this reason,
392 K.K. SHARMA et al.
intermittent (thrice-, twice- or once-a week) dosage
regimens are advisable when other antitubercular or
antileprotic drugs are used in combination with
rifampicin. The success of directly-observed-treat-
ment-strategy (DOTS) programme for the treatment
of tuberculosis and leprosy has been possible only
after understanding the PAE of rifampicin and its
synergistic prolongation of PAE of other antitubercular
and antileprotic drugs17. To explain the mechanism
of action of PAE, it has been suggested that an al-
teration of DNA function is possibly responsible for
this effect, since most inhibitors of protein and nu-
cleic acid synthesis (aminoglycosides, fluoroquino-
lones, tetracyclines, clindamycin, certain newer
macrolides/ketolides, and rifampicin and rifabutin)
induce long-term PAE against susceptible
bacteria18-21. Such a suggestion gets further credence
with the observation that cell wall active agents (beta-
lactams and vancomycin) either have no or very short
PAEs against most Gram-negative bacilli or induce
PAEs of about 2 hr against staphyllococci19. Other
mechanisms to explain PAE include post-antibiotic
leukocyte enhancement (PALE) and exertion of
antibacterial activity by post-antibiotic sub-MIC
effects20-23. The drug concentration below the MIC
have not only been shown to exert the inhibition of
bacterial growth to induce PAE but also to alter mi-
crobial cell morphology to produce a suppression of
virulence factors. The latter effect is another form of
PAE, and has recently been shown by Ohta and
coworkers and designated as the post-antibiotic sup-
pression effect (PASE)24. The ability of an antibiotic
to exhibit PAE, PALE or PASE on a particular organ-
ism is a theoretically attractive attribute, since anti-
biotic concentrations could fall below the MIC for the
bacterium yet remain effective to suppress the growth
or virulence of the pathogen. Results of a number of
clinical trials have shown the importance of PAE in
choosing the wide dosage intervals of such an anti-
biotic 5,15,19.
Concentration-dependent versus time-dependent
killing (CDK vs TDK) efficacy of antibacterial
agents
Bacterial cell death following antibiotic exposure can
be classified as either concentration-dependent or
concentration-independent (or time-dependent). Al-
though the bactericidal activity of a given antibiotic
is a function of several factors, viz. the selected an-
tibacterial drug, the pathogen species, and the expo-
sure concentration, it is generally accepted that kill-
ing profile is always the same, i.e. the agent always
shows CDK. However, some antibacterials display a
ceiling effect to this CDK, i.e. once a serum concen-
tration for near maximum effect is reached it is more
important to sustain it rather than increase the con-
centration. Agents showing this kind of antibacterial
effect have been suggested to exhibit the TDK dy-
namics. When integrating the microbiological activity
and pharmacokinetics of an antibiotic, several phar-
macological parameters appear to be significant mark-
ers of drug efficacy. The pharmacokinetic parameters
of area under the time-concentration curve (AUC),
maximum observed concentration (Cmax or peak con-
centration) after its administration and elimination half-
life (t1/2) are often integrated with a pharmacodynamic
parameter, MIC or MBC for the pathogen to generate
several integrated pharmacodynamic clinical mark-
ers of antibacterial efficacy, such as:
i) AUC/MIC ratio (also termed area under mini-
mum inhibitory concentration [AUIC]). If a round
the clock 24 h AUC is used to deduce this ratio,
it is called AUIC(0-24).
ii) Cmax/MIC ratio (also known as inhibitory quo-
tient).
iii) t>MIC or t>MBC, i.e., the time (t) measured
as per cent of time during which the concen-
tration remains above the MIC between the
two-dosage interval (total interval time taken
as 100 per cent).
Integration between pharmacokinetic and -dynamic
parameters is not surprising as both parameters have
been related to the efficacy of antibiotic. As a result,
it is often difficult to correlate a single pharma-
codynamic parameter to the efficacy of an antibiotic.
If it is assumed that the amount of drug delivered at
the site of infection, i.e. available to the pathogen
environment is proportional to the amount of drug de-
livered to the host (AUC), it can be concluded that
the AUC is the primary pharmacokinetic parameter
associated with antibacterial efficacy. Although AUC
is considered as the primary pharmacokinetic param-
eter, this entity is a product of concentration and time.
Therefore, under certain conditions, the influence of
concentration appears to be a predominant factor,
whereas under different set of conditions, the time

of exposure to the drug or the time >MIC or MBC
may play a larger role. For agents that exhibit CDK
and a relatively long PAE, viz. aminoglycosides,
fluoroquinolones and metronidazole, the influence
of t>MIC is small when compared with the influence
of Cmax. If an antibacterial agent does not exhibit
CDK and does not produce sustained PAE (e.g. beta-
lactams, which demonstrate TDK with no or minimal
PAE; actually β-lactam antibiotics exhibit moderate,
about 2 hr PAE against staphylococci and other Gram-
positive bacteria but negligible PAE against Gram-
negative bacteria, except carbapenems which have
some PAE for these organisms), the time of expo-
sure or the t>MIC contributes more to the killing proc-
ess than does drug Cmax.
Pharmacodynamic classification of antibiotics
Antibacterial agents can be classified into three groups
on the basis of their pattern of bactericidal activity as
shown by their CDK or TDK dynamics and whether
they exert persistent PAE, PALE or PASE (Table 1).
Group I. Agents that show concentration-
dependent killing (CDK) efficacy with
persistent PAE
Aminoglycosides, fluoroquinolones, metronidazole
and other nitroimidazoles display CDK pharmaco-
dynamics with a prolonged and persistent PAE. All
these agents eliminate bacteria more rapidly when
their concentrations are appreciably above the MIC
of the organism, i.e. the rate of bactericidal activity is
maximum at the peak serum concentration (Cmax)12,15.
As the drug concentration decreases, the rate of an-
tibacterial activity decreases. Higher doses of the drug
increase the peak and all subsequent drug levels,
and thus there is not only an increase in the rate and
extent of bacterial killing but also in length of time of
drug exposure to bactericidal concentrations. This
implies that the clinical efficacy of this group of agents
is influenced by both the Cmax, and the AUC consid-
ered in relation to MIC. Since agents of this group
display a powerful PAE, duration of which is also con-
centration (Cmax and AUC profile) dependent, the re-
sidual bacterial population is less at the time of next
dose. This suggests that wide dosage intervals can
be chosen with this group of drugs. With respect to
aminoglycosides, landmark studies of Moore et al 25
(other studies cited therein) suggested that Cmax/MIC
ratio of at least 8 to 10 were necessary for achieving
an optimal clinical response in 90% of patients treated
NEW CONCEPTS IN ANTIBACTERIAL THERAPY 393
for Gram-negative bacterial infection. In addition, Cmax/
MIC ratios of this magnitude in another study pre-
vented the development of resistance26. This sugges-
tion gets further credence from a previous study by
Keating et al 27 who observed an aminoglycoside re-
sponse rate of 57%, 67% and 85% in neutropenic
patients with mean serum Cmax/MIC ratios of 1 to 4, 4
to 10, and greater than 10, respectively. Taken to-
gether, several investigators have opined that both
Cmax/MIC ratio and the AUC/MIC ratio are effective
predictors of therapeutic outcome in patients receiv-
ing aminoglycosides19.
Accordingly, to take advantage of the CDK and PAE
dynamics of aminoglycosides, the concept of once-
daily dose regimen has been introduced in clinical
practice28. The drug is administered in a single dose
(gentamicin, 7 mg/kg, q 24 h) rather than in divided
doses (1.5 mg/kg, q 8 h) over a 24 h period. Similarly
the promoted single dose for tobramycin and
netilmycin is in this range, whereas for amikacin it is
10-20 mg/kg. The single dose regimen optimizes the
bactericidal activity and reduces potential toxicity of
aminoglycosides by taking advantage not only of its
CDK ability but also of two other important character-
istics, i.e. time-dependent toxicity and prolonged con-
centration-dependent PAE29,31. Besides being safe and
effective, once-daily regimen of aminoglycosides also
reduces the cost on therapeutic drug monitoring and
injection devices28.
For fluoroquinolones Forrest et al.32 by using cipro-
floxacin for serious infections found that clinical and
bacteriological response rates of <50% were achieved
(in 7 days) when the AUIC(0- 24) was <125. However,
when a higher AUIC(0- 24) (>250) was obtained, the
response rate rose to 80% within 2 days. Thus, these
results suggest that antibiotics which show CDK effi-
cacy, an AUIC(0- 24) of >125 can achieve a better and
rapid clinical cure using dosage regimens that pro-
duce high initial concentrations. Further emergence
of resistance can be prevented if doses of these
agents that optimize the values of C max/MIC or
AUIC(0-24) are used26,33.
Group II. Agents that show time- (or duration)
dependent killing (TDK) efficacy with
minimal PAE
β-lactam antibiotics, clindamycin, and macrolides,
except azithromycin exhibit TDK with minimal PAE.
394 K.K. SHARMA et al.

Table 1. Pharmacodynamic classification of various antibacterial agents which determine their dosage regimens for efficient clinical
use along with pharmacodynamic markers to measure clinical efficacy

Antibacterial Aim of dosage Pharmacodynamic marker(s)

agent regimen for of clinical antibacterial
efficient use efficacy*

I. Agents with concentration-dependent killing with persistent PAE

1. Aminoglycosides Maximise drug concentration Peak concentration (Cmax)/
2. Fluoroquinolones (applicable to 1 to 4) MIC ratio (should be >8-10)
3. Metronidazole 24 h AUC/MIC ratio
[AUIC(0- 24) which should be >125 for
Gm-negative bacilli and considerably
less, perhaps 25-50 for S. aureus/S.
pneumoniae]
4. Streptogramins (applicable to 1 to 4)
a. Quinupristin/Dalfopristin
(Synecid)
II. Agents with time (duration)-dependent killing with short or no PAE
1. β-lactam antibiotics Maximise exposure time t>MIC or MBC
a. Penicillins (applicable to 1 to 4) (applicable to 1 to 4)
b. Cephalosporins
c. Carbapenems**
d. Aztreonam
2. Macrolides***
3. Clindamycin
4. Oxazolidinones
a. Linezolid
b. Eperezolid
III. Agents with time (duration)-dependent killing with persistent PAE
1. Macrolides Maximise daily amount of dose t>MIC or MBC
a. Azithromycin (applicable to 1 to 4) (applicable to 1 to 4)
b. Clarithromycin 24 h AUC/MIC ratio (only for
newer macrolides and tetracyclines)
2. Ketolides
a. Telithromycin (HMR 3647)
3. Tetracyclines
4. Vancomycin

*for abbreviations see text; **show short-duration PAE; ***except azithromycin, clarithromycin and other newer macrolides.

With these agents, the bactericidal activity is not
enhanced by increasing the concentrations above
MIC or MBC and the action is relatively slow. The
bacterial killing rate reaches a ceiling at serum
concentrations about 4 to 5 times the MIC and bac-
terial growth promptly resumes when serum and tis-
sue concentrations fall below the MIC because there
is either no or short PAE for most of this group of
agents4,34,35. Therefore, in this group the time needed
for serum concentrations to exceed the MIC or MBC

is an important determinant of efficacy. Thus the aim
of therapy with these agents is to maintain serum
concentrations above the MIC or MBC for as long as
possible during the dosing intervals. Although the in-
fecting organisms are located in the interstitial space,
drug concentrations in the interstitial fluid are gener-
ally in equilibrium with that of serum. Thus, by in-
creasing the time duration when serum levels remain
above the MIC, would concomitantly increase the drug
concentration proportionally at the site of infection.
Although there is no consensus on the optimal dura-
tion of time that serum antibiotic concentration should
remain above the MIC, it has been observed that the
range of suprainhibitory serum concentration for
40 to 50% of the duration of dosage interval provide a
minimum threshold for this group of agents5,11,35-36.
This view is supported by the study of Schentag
et al.37 who reported that in patients with nosocomial
pneumonia the number of days of cefmenoxime
therapy required to eradicate pathogens from sputum
was inversely correlated with the proportion of time
during which serum drug concentrations exceeded the
MIC. Ten to 13 days treatment was required if con-
centrations exceeded the MIC for less than 50% of
the dosage interval, whereas this time was reduced
to between one and six days when drug concentra-
tions exceeded the MIC for all or most of the dosage
intervals37. Supporting observations from other stud-
ies38,39 further reiterate that for maximal efficacy, se-
rum drug levels of this group of agents had to be
above the MIC for nearly all of the 24 h treatment
period. Since, the optimal duration of dosage interval
for a given antibiotic varies depending upon the in-
fecting organism, site of infection, inoculum effect,
and immunocompetence of the host, with this con-
cept, it is clear that the pharmacodynamic marker:
t >MIC with an efficacy break point value of >50% is
important for clinical success with this group of anti-
biotics; closer is the value towards 100%, greater will
be the success rate. For β-lactams with short half-
lives, it is important to maintain drug concentrations
above the MIC against infecting pathogens during most
of the dosage interval. This can be done by using
smaller fractions of the total daily dose given at fre-
quent intervals or the use of β-lactams with long se-
rum half lives such as ceftriaxone (t½ of 6-8 h). A
number of experimental and clinical studies compar-
ing efficacy of intermittent dosing with that of con-
tinuous infusion suggest the importance of this ap-
NEW CONCEPTS IN ANTIBACTERIAL THERAPY 395
proach for successful treatment of serious infections
with β-lactam drugs34,40-42. In a study, Bodey et al.43
compared carbenicillin plus either intermittent or con-
tinuous infusion cefamandole in febrile cancer pa-
tients. Evaluation of 235 infections revealed that 65%
receiving continuous infusion were cured against 57%
receiving intermittent dosing. In addition, the continu-
ous infusion regimen was significantly (p=0.03) more
effective (65% cure) than intermittent regimen (21%
cure) for the treatment of infections in profoundly
neutropenic patients43. Data concerning with continu-
ous infusion studies further reiterate the importance
of t>MIC and suggest that maintaining the MIC for
the entire dosing interval should ensure optimal effi-
cacy with very short half life antibacterial agent that
show TDK dynamics with minimal PAE3-5,40-43. Besides,
the concept of t>MIC can be used to compare the
effectiveness of different time-dependent antibiotics
within a class, and as a corollary those drugs having
lower MIC, i.e. greater potency would be anticipated
to have longer time above MIC and therefore greater
effectiveness.
Group III. Agents that show time- (duration)
dependent killing (TDK) with pro-
longed PAE
Antibacterial drugs, such as newer macrolides, e.g.
azithromycin, clarithromycin, etc., vancomycin, and
tetracyclines, like agents of Group II exhibit TDK effi-
cacy but differ in that they have a prolonged and per-
sistent PAE. For these agents, although the duration
of antibacterial exposure is important, clinical efficacy
is not compromised if concentration falls below the
MIC as they possess persistent PAE. Thus for this
group of agents both t > MIC and 24 h AUC/MIC ratio
[AUIC(0-24)] play an important role in planning the dos-
age regimens44. For vancomycin, when used for se-
vere life threatening situations t>MIC marker is more
important; otherwise for azithromycin, clarithromycin
and tetracyclines, and even vancomycin when used
for less severe infections AUIC(0-24) can be used as
pharmacodynamic marker to predict the antibacterial
concentration at the infection site1,44.
The PAE-inducing property of vancomycin appears
to be related to its hitherto unimportant inhibitory ef-
fect on RNA synthesis45, since another glycopeptide
antibiotic teicoplanin which acts as bactericidal, like
vancomycin by inhibiting cell wall synthesis, does
not show this effect.
396 K.K. SHARMA et al.

Table 2. Recommended dosage intervals for parenteral anti- ministration (vide supra)26,28-31. There is also evidence
microbial agents in the treatment of serious infec- that administration of subsequent aminoglycoside
tions.
doses, while there is still detectable aminoglycoside
Agents that can be given once daily present, may inhibit their bacterial killing capacity.
This phenomenon is called "adaptive resistance af-
1. Aminoglycosides
ter first exposure". Bacteria are no more sensitive to
2. Ceftriaxone
bactericidal activity for several hours before gradu-
3. Vancomycin*
ally returning to their full sensitivity46-47. The mecha-
4. Teicoplanin
nism for this adaptive resistance is thought to be
5. Pefloxacin
down-regulation of aminoglycoside uptake by energy-
6. Fleroxacin
dependent drug transport into the bacterial cell46.
Agents that can be given twice daily
Accordingly the once daily dose regimen of
1. Cefazolin† aminoglycoside antibiotics appears to be more
2. Cefotetan rational.
3. Cefonicid
4. Cefepime*
As discussed above for β-lactams, it is important to
maintain drug concentration above MIC against the
5. Cefpirome*
infecting pathogen over much of the dosage interval.
6. Meropenem†
Therefore, agents with long half-lives can be given
7. Synecid* less frequently (Table 2), e.g. ceftriaxone which has
Agents usually given three-times daily the longest half-life among the β-lactams (approxi-
1. Cefazolin mately 8-10 h) can be given once daily. Cefotetan,
2. Cefotaxime cefoperazone and cefonicid have t½ of >2 h and can
3. Ceftazidime be given twice daily. Cefazolin, cefotaxime,
4. Aztreonam ceftazidime and aztreonam have short t½ of 1 to 2 h
5. Carbapenems and generally need to be given 3-times daily42. Other
6. Most penicillins cephalosporins and penicillins have a half-life of only
Agents that can be given by continuous infusion 0.5 to 1 h and are generally required to be given 4
times daily or more frequently.
1. Beta-lactams
The carbapenems (imipenem+cilastatin; meropenem;
*In very severe or life-threatening situations including bacter-
biapenem) also have short half-lives of approximately
aemia, especially in immunocompromised patients (difficult-to-
treat infections in critically ill patients with normal renal function) 1 h, thus, 3 times-daily administration may not pro-
an 8 h (8 gm, q8h) dose is advised. vide concentrations above the MIC through-
†
Less-frequent administration is found to be effective. out the dosage interval. However, since these agents
show some amount of PAE albeit of short duration1,
this persistent effect allows a longer dosage interval.
Indeed, twice-daily administration of meropenem has
Other drug and disease-related pharmacokinetic been shown to be as effective as 3-times daily ad-
factors in selection of antibacterials and their dos- ministration in patients with urinary tract infection or
age respiratory tract infections48 as has been twice daily
administration of cefazolin for cellulitis49.
Since aminoglycosides have half-lives ranging be-
tween 2 and 8 h, it may be difficult to obtain Cmax/MIC Certain disease states, such as sepsis and burns
ratio of >8-10 h, i.e. peak concentration 8-10 times produce hyperdynamic circulation where there may
greater than the MIC without reaching toxic concen- be an increase in volume of distribution, glomerular
tration. Since, these ratios are also important in pre- filtration and rapid renal elimination of certain antibi-
venting the development of resistance, there is cur- otics50. Therefore, drugs whose MIC can be affected
rently a trend towards single daily administration15,26. by such a change in haemo-renal dynamics
This regimen has been shown to be more effective (aminoglycosides, cephalosporins and vancomycin,
and possibly less toxic than traditional 8-hourly ad- etc.) should be administered initially during the course

of the disease in high doses, i.e. on day 1 and/or 2.
Later the dose and/or frequency of administration, as
the patient condition improves, may be down-
graded 50,51. The antibacterial effectiveness of
aminoglycosides is diminished by low pH, oxygen ten-
sion and osmolality, an intrinsic environment always
present at the site of infection, specially if the latter
also involves anaerobic microorganisms, e.g. intra-
abdominal sepsis. In such situations and other mixed
(aerobic-anaerobic) infections, an aminoglycoside
agent should be combined with an appropriate β-
lactam or glycopeptide antibiotic to limit the spread
of infection and tackle Gram-negative septicaemia.
Also in mixed infections such a combined use would
break aerobic-anaerobic synergy for optimal outcome.
Conclusion
Clinically, pharmacodynamic effects of antibacterial
agents are difficult to assess because of the intrica-
cies in determining the bacterial load at the site of
infection and antibiotic concentrations repetitively
during the dosing interval. However, these difficulties
can be overcome by understanding the pharmaco-
dynamic factors in developing optimal treatment strat-
egies as has been confirmed in a number of studies
using models of infection in animals and clinical situ-
ations. These models attempt to simulate human in-
fections and can predict how best the microbiological
activity (an in vitro phenomenon) and antibacterial
pharmacokinetic data in host (in vivo parameters) can
be used to select an antimicrobial agent as well as
its dosage regimen for successful therapy of infec-
tion. It can be deduced from these models that the
requirement for bactericidal therapy for bacterial
endocarditis, meningitis and developing synergistic
combinations to treat enterococcal septicaemia or to
shorten the course of antibacterial therapy it is nec-
essary to obtain Cmax/MIC ratios greater than 10, or
24 h, AUC/MIC ratios greater than 125 for antibiotics
that show concentration-dependent killing dynamics,
and time above the MIC longer than 40 - 50% of the
dosing interval for agents that exhibit time-depend-
ent killing dynamics. If an agent shows considerable
PAE, the dosage interval can be less stringent as
compared to those which show minimal PAE. These
pharmacodynamic models provide a unique approach
to determine the likely in vivo activity of individual
antibacterial agents and prediction of clinical out-
comes.
NEW CONCEPTS IN ANTIBACTERIAL THERAPY 397
Acknowledgement
The Authors are grateful to Prof. S. Dwivedi, Depart-
ment of Medicine, University College of Medical
Sciences & GTB Hospital, Delhi and the two anony-
mous peer reviewers for thoughtful critique, useful
feedback and suggestions regarding this paper.
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NEW CONCEPTS IN ANTIBACTERIAL THERAPY 399
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